APOBEC3 deaminases are a critical component of the innate immune system by restricting foreign, pathogenic DNA primarily through the purposeful mutation of single-stranded DNA cytosines to uracils. The DNA editing activities of the APOBEC3 family relies on Zn<sup>2+</sup>-activation of water in the enzyme active site, which then participates in the hydrolytic deamination of the 4-NH<sub>2</sub> of cytosine, yielding uracil. Aberrant activities of members of the APOBEC3 family have demonstrated crucial roles in human disease, such as contributions of mutations to virus (APOBEC3D/F/G/H) and cancer (APOBEC3A/B/H) genomes. Consequently, potent and selective chemical probes of the 7 APOBEC3 family members are desired. To address this unmet need, we have utilized small molecule-, fragment-, and computation-based screening to identify early APOBEC3 inhibitors that can be optimized into chemical probes through iterative cycles of structural refinement. Two early, albeit reactive, inhibitors found by small molecule high-throughput screening, MN30 and MN256, helped to characterize Cys321 of APOBEC3G as a hot spot for covalent binding by electrophilic compounds that results in inhibition of deaminase activity. More recently, we have exploited two x-ray co-structures of APOBEC3-DNA complexes to rationally design nucleic acid-based inhibitors. Our efforts to develop chemical probes of the APOBEC3 family of DNA deaminases based on small molecule and nucleic acid platforms will be presented.

Discovery of small molecule and nucleic acid inhibitors of APOBEC3 deaminases

255th National Meeting (2018)

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